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Medizinische Universitäts-Poliklinik, 53111 Bonn, Germany
Low-density lipoprotein (LDL) is known to be a mitogenic factor
for vascular smooth muscle cells (VSMCs), fibroblasts, and endothelial cells. In the current study, we describe possible intracellular mechanisms by which LDL elicits its mitogenic effects. Stimulation of VSMCs with LDL resulted in a pertussis-toxin
(PTX)-sensitive stimulation of the 44-kDa mitogen-activated protein
(MAP) kinase (p44mapk) and 42-kDa MAP kinase
(p42mapk) isoforms as well as in a PTX-sensitive increase
in intracellular free Ca2+ concentration
([Ca2+]i). Binding of the LDL-induced
increase in [Ca2+]i to the intracellular
Ca2+ chelator
bis(2-amino-5-methylphenoxy)ethane-N,N,N
,N-tetraacetic acid tetraacetoxymethyl ester resulted in a 2-fold increase in the
phosphorylated p44mapk and p42mapk isoforms but
did not influence the LDL effect of VSMC DNA synthesis. PD 98059, a MAP
kinase kinase inhibitor, remarkably attenuated the LDL-induced
activation of MAP kinases and DNA synthesis. Treatment of normal human
skin fibroblasts and human fibroblasts isolated from patients with
familial hypercholesterolemia homozygote class 1 mutations, which are
not able to produce the classic LDL receptor, resulted also in a
PTX-sensitive increase in cell DNA synthesis and stimulation of the
p44mapk and p42mapk isoforms in both cell
types. These results demonstrate that the mitogenic effect of LDL is
mediated by a PTX-sensitive Gi-coupled receptor that is
independent of its classic receptor and involves activation of MAP
kinase isoforms. Furthermore, the mitogenic effect of LDL may be
mediated by the activation of the MAP kinase pathway. In contrast, the
LDL-induced increase in [Ca2+]i may be
implicated in this process only in conjugation with other signaling
components.
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